Telomeres are essential and functional components of the physical ends of eukaryotic chromosomes (Blackburn 1991; Greider 1996). Telomeres enable cells to distinguish chromosome ends from double-strand breaks in the genome. Without functional telomeres, the chromosomes are prone to nucleolytic degradation leading to cell death through apoptosis and may rearrange by genetic recombination or end-to-end fusion (Counter et al. 1992; Blasco et al. 1997; Artandi et al. 2002). Most normal human somatic cells show a progressive loss of telomeric DNA during successive rounds of cell division due to a DNA end replication problem (Lingner et al. 1995). Thus, telomere shortening has been proposed as a ticketing mechanism that controls the replicative capacity of cells and cellular senescence (Harley 1991). Cells with extended replicative life spans have mechanisms to counteract loss of telomeric DNA. In most human cancer cells, telomere shortening is alleviated by telomerase, a ribonucleoprotein enzyme that is composed of a catalytic subunit, hTERT, and its template RNA, hTR (Blackburn 1992; Counter et al. 1992). Telomerase activity is detectably expressed in the majority of human cancer cells but is repressed in most normal somatic cells (Kim et al. 1994). Since introduction of hTERT gene into normal somatic cells extends the life-span of the cells, the immortalized phenotype of most cancer cells would involve activation of telomerase (Bodnar et al. 1998).
Telomerase activity correlates with hTERT expression, implicating this catalytic subunit as the rate-limiting component of the telomerase holoenzyme (Nakamura and Cech 1998). Although telomerase activity is regulated by gene expression for hTERT (Wang et al. 1998; Wu et al. 1999; Meyerson et al. 1997), several lines of evidence have suggested a post-translational regulation of telomerase activity. One possible mechanism for the post-translational modification of telomerase is the interaction of hTERT with accessory proteins such as enzymes, chaperones, and polypeptide modifiers (Lee et al. 2004; Liu 1999; Zhou and Lu 2001). Recent studies have shown that the molecular chaperone Hsp90 binds specifically to hTERT to promote the assembly of active telomerase both in a cell-free system and in intact cells (Holt et al. 1999). Moreover, inhibition of Hsp90 function in cells blocks assembly of active telomerase. However, the underlying mechanism has not been elucidated.
Identifying cellular mechanisms that control the activity of telomerases may provide new and helpful targets for establishing new cancer therapy agents.